Grant Award Details

To develop approaches to characterize and transplant endogenous hMuSC and to perform pre-clinical studies that will provide the basis for IND-enabling studies to develop hMuSC as a therapeutic. A specific target disease has not been specified. In consideration are muscle ailments that present an important unmet clinical need but only affect small isolated muscles that could be regenerated with localized transplantation of relatively small numbers of cells. Examples include: 1) atrophy and muscle dysfunction in the face or hand after nerve injury or direct trauma that does not recover after reinnervation. 2) extraocular muscle injury causing inability to move the eye and diplopia seen in Graves’ disease, traumatic injury, oculopharyngeal muscular dystrophy and progressive external ophthalmoplegia. 3) urinary and fecal incontinence, for which therapies that address the small sphincter muscles involved have great potential.

Progress Reports

Reporting Period:

Year 1

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In the first year of the New Faculty Physician Scientist award, my colleagues and I have made progress on all 3 Aims. The majority of our focus in accordance with our planned timeline has been on Aim 1, where we have made the most significant progress and are preparing our first manuscript based on Aim 1 results. Aim 1 focuses on identification of appropriate donor muscles for human muscle stem cell applications. We are using the backdrop of knowledge that we have concerning mouse muscle stem cell biology to study human muscle stem cells. As human muscle stem cells have not been definitively characterized or transplanted, the initial main focus of this CIRM grant is to do so with stem cells from diverse muscles and, combined with our clinical understanding of expendability of different muscles, choose human muscles that will be appropriate to harvest stem cells from in future applications. For the experiments in Aim 2, we are testing injury and transplantation methods for human muscle stem cells that could potentially be used clinically. We have also begun work on Aim 3, developing preclinical models in which to test human muscle stem cell transplantation.

Reporting Period:

Year 2

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In the first two years of the New Faculty Physician Scientist award, my colleagues and I have made progress on all 3 Aims. The majority of our focus in accordance with our planned timeline has been on Aim 1, where we have made the most significant progress and have completed the Aim. Aim 1 focuses on identification of appropriate donor muscles for human muscle stem cell applications. We have characterized and transplanted human muscle stem cells from diverse muscles and have evaluated their ability to engraft into recipient muscle. As human muscle stem cells have not previously been definitively characterized or transplanted, the initial main focus of this CIRM grant is to do so with stem cells from diverse muscles and, combined with our clinical understanding of expendability of different muscles, choose human muscles that will be appropriate to harvest stem cells from in future applications. We have now accomplished this and are positioned to complete the remaining Aims of the grant. For the experiments in Aim 2, we are testing injury and transplantation methods for human muscle stem cells that could potentially be used clinically and are testing the effects of human muscle stem cell transplantation on muscle function. We have also begun work on Aim 3, developing preclinical models in which to test human muscle stem cell transplantation.

Reporting Period:

Year 3

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In the third year of the New Faculty Physician Scientist award, my colleagues and I have made progress on all 3 Aims. The majority of our focus in accordance with our planned timeline has been on Aims 2 and 3, and we published our first manuscript based on Aim 1 results. Aim 1 focused on identification of appropriate donor muscles for human muscle stem cell applications and characterization of endogenous human muscle stem cells. As human muscle stem cells had not been definitively characterized or transplanted, the initial main focus of this CIRM grant was to do so with stem cells from diverse muscles and, combined with our clinical understanding of expendability of different muscles, choose human muscles that will be appropriate to harvest stem cells from in future applications. We have accomplished that and published the essential results in September 2015. For the experiments in Aim 2, we are testing injury and transplantation methods for human muscle stem cells that could potentially be used clinically and have made advances that will allow us to effectively test preclinical therapeutic approaches that are the subject of Aim 3. In the past reporting period work on Aim 3, has focused on developing preclinical models in which to test human muscle stem cell transplantation. We are characterizing these models in anticipation of testing human muscle stem cells in them in the next reporting period.

Reporting Period:

Year 5

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<p>Skeletal muscle makes up 40% of our bodies, dictates our form, is responsible for our ability to move, express ourselves, eat, breathe and to look around. Skeletal muscle injury and disease are major sources of morbidity that affect millions. The potential for treating these ailments with regenerative approaches that use stem cells is enormous because skeletal muscle naturally has its own stem cell population. To make human muscle stem cells a usable clinical tool we have, under this award, &nbsp;characterized them, transplanted them, and gained insights that will be used by clinicians to induce them to function effectively. To do this, we identified appropriate human muscles to harvest stem cells from, and developed techniques to transplant them. This has enabled us to test them in models of diseases. The work has resulted in new funding from the NIH for continuation of the research, and has resulted in the development of techniques to store and share endogenous human muscle stem cells with other researchers and clinicians. &nbsp;We plan to continue advancement of this research to develop &nbsp;treatments for patients with several disabling muscle degenerative conditions.&nbsp;</p><p data-empty="true"><br></p><p><br></p>

Reporting Period:

Year 6 NCE

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<p>Skeletal muscle injury and disease are major sources of morbidity that affect millions. The potential for treating these ailments with regenerative approaches that use stem cells is enormous because skeletal muscle naturally has its own stem cell population. However, to make human muscle stem cells a usable clinical tool we needed to be able to characterize them, transplant them, and induce them to function effectively. To accomplish these goals, our objectives of this project were to are to identify appropriate human muscles to harvest stem cells from, to develop techniques to transplant them, and to test them in models of diseases. The outcomes of the work resulted in characterization of muscle stem cells in various different human muscles, and the development of effective techniques to transplant the cells into muscles. Approaches were also developed to store and distribute these cells among researchers and eventually to patients. The effect of transplanting human muscle stem cells in animal models of several injuries and diseases was tested, providing insight into how muscle stem cells may be used to contribute to treatment of muscle diseases. The work has been published and additional publications are forthcoming. &nbsp;Invention disclosures have been filed. The career goals for this New Faculty award included development of a robust, innovative muscle stem cell research program for the PI that would create a sustainable combination of clinical and research activity involving ongoing translation from bench to bedside and from bedside to bench, and to yield pathways to new funding to launch additional projects that would develop from this one. These goals were also achieved. The PI has developed an independent federally funded research program in muscle stem cell and regeneration research. The research program of the PI can this continue with the gaol of furthering translational research aiming to treat muscle diseases and injuries.&nbsp;</p><p><br></p>

Grant Application Details

Skeletal muscle makes up 40% of our bodies, dictates our form, is responsible for our ability to move, express ourselves, eat, breath and to look around. Restoration or preservation of the body’s normal form and function is the central goal of regenerative medicine and the central focus of my clinical specialty of plastic and reconstructive surgery. Skeletal muscle injury and disease are major sources of morbidity that affect millions. The potential for treating these ailments with regenerative approaches that use stem cells is enormous because skeletal muscle naturally has its own stem cell population. However, to make human muscle stem cells a usable clinical tool we need to be able to characterize them, transplant them, and induce them to function effectively. To accomplish these goals, our objectives are to identify appropriate human muscles to harvest stem cells from, to develop techniques to transplant them, and to test them in models of diseases. This work is expected to lead directly to treatments for patients with several disabling muscle degenerative conditions that affect small but critical muscles that could be regenerated with localized muscle stem cell transplants. Examples include facial paralysis or loss of hand function, and conditions affecting the eye muscles causing vision loss. This work also lays the groundwork for tissue engineering of muscles, and will contribute to approaches to correct genetic muscle defects or treat other systemic muscle diseases.

Statement of Benefit to California:

Skeletal muscle injury and disease are major sources of morbidity that affect Californians of all ages, including the veteran population. Regenerative medicine and stem cell biology offer great potential for opportunities to improve upon current treatments and to develop approaches for many of the muscle ailments that remain essentially untreatable. Skeletal muscle stem cells have been well characterized in mice, and preliminary evidence suggests similar approaches in humans will enable clinical translation. Therefore, the proposed research seeks to develop stem cell therapies that will directly impact muscle ailments that are at the root of diverse deformities and disabilities of the face, body and limbs. California is the birthplace of many of the great advances in reconstructive surgery, including microsurgery and muscle flaps, largely through the support of its people, and their pioneering spirit. In turn, Californians have benefited and continue to benefit from the newest and best approaches that reconstructive surgery has to offer. We propose to continue to improve reconstructive and regenerative options for the citizens of California by building on our strong historical foundation to address current needs. Our research will carry on this tradition because of our focus on problems of form and function affecting many of our citizens, the logical path to muscle stem cell clinical application, and the unique clinical and scientific focus and potential of our team.